This continuing research project is intended to comprehensively determine the specific mechanisms which result in resistance to the action of insulin in a common human syndrome characterized by the acanthosis nigricans skin lesion and marked endogenous hyperinsulinemia. The most common presentation of this condition is at puberty in females who also have obesity and oligomenorrhea. In young adolescents, glucose tolerance is often normal in spite of severe insulin resistance but recent data suggests that there is frequently progressive loss of compensatory insulin hypersecretion and the eventual development of non-insulin dependent diabetes mellitus (NIDDM). Further data suggests this dramatically increases incidence of the skin lesion among some minority groups. The long term goals of this project are (a) to fully characterize the nature of the resistance to insulin, (b) to delineate the relative importance of genetic and acquired factors in this syndrome, (c) to determine the relationship of the ovarian dysfunction and the skin lesions to the insulin resistance, and (d) to determine what therapy can be effective in ameliorating this condition. The short term goals in the next year are to test the following hypotheses. (1) Many of these subjects with severe insulin resistance have one or more point mutations within functional domains of the insulin receptor. To test this hypothesis we will determine the exact gene sequence of limited portions of insulin receptor gene corresponding to the tyrosine kinase domains. (2) The acanthosis nigricans skin lesion which we have documented to have a high prevalence in the general population is always a marker for severe endogenous hyperinsulinemia which is in compensation for insulin resistance, either acquired or inherited. This hypothesis will be pursued by evaluating the insulin sensitivity of every patient identified with acanthosis nigricans. (3) This insulin resistance syndrome has as its natural course to loose pancreatic beta cell reserve and eventually develop overt NIDDM. This will be tested by performing yearly follow-up assessments in all identified patients, consisting of determining glucose tolerance and quantitating insulin secretion and insulin responsiveness. Additional data will be maintained on the course of the obesity, ovarian dysfunction, hypertension, and hyperlipidemia. (4) Evaluation of potential insulin receptor defects in each parent of severely affected patients will reveal one or more specific structural abnormalities. This suggestion will be tested by evaluating insulin receptor structural properties, insulin receptor gene expression, and insulin receptor gene structure in the parents of twelve severely affected patients identified to have a specific structural defect. These proposed experiments may provide important insight into mechanisms of defective insulin action in other common health problems such as obesity and NIDDM.